Miller A L, Medina M A
Department of Psychiatry, University of Texas Health Science Center at San Antonio 78284.
Metab Brain Dis. 1986 Jun;1(2):147-56. doi: 10.1007/BF00999384.
Rats treated intravenously with an organophosphorus anticholinesterase compound, paraoxon or soman, were sacrificed 2 to 131 min later, using 0.7 sec of focused microwave irradiation (25 kW at 915 MHz). Brain regional rates of glucose utilization during 3-min intervals were determined with labeled glucose and fluorodeoxyglucose as tracers. Levels of glucose, lactate, ATP, and creatine phosphate were assayed in the same samples. The two compounds differed markedly in their effects on brain metabolism. Paraoxon (0.8 LD50) depressed rates of glucose use in all brain regions, without causing consistent changes in brain metabolite levels. This depressant effect was most pronounced during the first 30 min after toxin exposure and had largely disappeared by 2 hr. Soman (0.8-0.95 LD50) was variable in its effects. Animals that showed seizure-like behavior had marked increases in glucose use in diencephalon and cerebrum but no changes in cerebellum or brain stem. Rapid rates of glucose use were associated with high levels of lactic acid and lower levels of creatine phosphate. In cerebrum, but not diencephalon, levels of ATP fell by as much as 50% in strongly affected animals by 30-130 min after soman. All of these effects were reversible with atropine. Soman-treated animals that did not have seizure-like activity did not exhibit these brain metabolic changes. These results and those of others show that cholinergic compounds vary greatly in their effects on brain glucose and energy metabolism. Although noncholinergic mechanisms are a possibility, the most parsimonious explanation for these findings is that cholinesterase inhibitors vary in their affinity for different central nervous system (CNS) acetylcholine receptor populations.
给大鼠静脉注射有机磷抗胆碱酯酶化合物对氧磷或梭曼，2至131分钟后使用聚焦微波照射0.7秒（915兆赫，25千瓦）将其处死。以标记葡萄糖和氟脱氧葡萄糖作为示踪剂，测定3分钟间隔内脑区葡萄糖利用率。在相同样本中检测葡萄糖、乳酸、三磷酸腺苷（ATP）和磷酸肌酸的水平。这两种化合物对脑代谢的影响显著不同。对氧磷（0.8半数致死剂量）使所有脑区的葡萄糖利用速率降低，而脑代谢物水平未出现一致变化。这种抑制作用在毒素暴露后的最初30分钟最为明显，到2小时时基本消失。梭曼（0.8 - 0.95半数致死剂量）的影响则各不相同。表现出癫痫样行为的动物，间脑和大脑的葡萄糖利用显著增加，而小脑或脑干则无变化。葡萄糖快速利用与高乳酸水平和低磷酸肌酸水平相关。在大脑中，但间脑未出现，在梭曼作用后30 - 130分钟，受强烈影响的动物中ATP水平下降多达50%。所有这些影响均可被阿托品逆转。未表现出癫痫样活动的梭曼处理动物未出现这些脑代谢变化。这些结果以及其他研究结果表明，胆碱能化合物对脑葡萄糖和能量代谢的影响差异很大。尽管非胆碱能机制是一种可能，但对这些发现最简洁的解释是胆碱酯酶抑制剂对不同中枢神经系统（CNS）乙酰胆碱受体群体的亲和力不同。
